Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
  • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
  • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
  • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
  • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
  • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
  • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
  • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D241/18—Oxygen or sulfur atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
  • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
  • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
  • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
  • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms

Definitions

• R R and R are selected from the class consisting of hydrogen and lower alkyl, lower alkoxy, trifluoromethyl, fluoro, chloro, bromo and nitro groups, or R and R are combined in a methylene dioxy group;
• R and R together with the nitrogen atom form a member selected from the group consisting of Z-morpholino, Z-thiomorpholino, Z-piperidino and Z-pyrrolidino, wherein Z is selected from the group consisting of hydrogen and lower alkyl;
• R is selected from the class consisting of hydrogen and lower alkyl groups
• X and Y are alkylene chains, either straight or branched,
• the acid addition salts of the above compounds have been found to be valuable antitussive agents, devoid of undesirable side-effects. Such compounds and their acid addition salts are especially valuable because of the absence of analgesic properties and local anesthetic effects when administered in active dosages.
• the most valuable compounds are those in which stands for a 4-morpholino group, whether or not loweralkyl-substituted.
• l R2 R1 X is an alkylene group with one carbon atom less than X.
• X and Y represent alkylene groups with one carbon atom less than X and Y, respectively.
• R is a lower alkyl group
• Compounds in which R is a lower alkyl group can be prepared by alkylation of the corresponding secondary amines, in accordance with either of the following methods! (a) Addition of a lower aliphatic carbonyl compound to the secondary amine and reduction of the adduct by suitable reductive agents, such as, formic acid or catalytic hydrogen.
• Example 1 A solution of 17.05 grams of phenoxyacetyl chloride in 150 ccs. of dry benzene is added slowly to a solution of 13.1 grams of 4-(2-aminoethyl)-morpholine in 150 ccs. of dry benzene while stirring and cooling with water.
• Example 2 A solution of 13.2 grams of the free base obtained above in a mixture of 125 ccs. of benzene and 50 ccs. of diethyl ether is added dropwise, with stirring, to a solution of 5 grams of lithium aluminum hydride in 75 ccs. of diethyl ether. The rate of addition is such that the reaction-mixture keeps boiling of its own. Refiuxing and stirring is continued for 16 hours.
• Example 3 A mixtureof 3.23 grams of 4-[2-(2-phenoxyethylamin)et-hyl]-morpholine dihydrochloride, 1.36 grams of sodium formate, cos. of formic acid (98%) and 4.7 ccs. of an aqueous formaldehyde solution (36%) is heated for about 30 minutes on a steam bath with stirring, until the evolution of carbondioxide has ceased. The cooled solution is made strongly alkaline by addition of a concentrated potassium hydroxide solution and xtracted repeatedly with benzene.
• Example 4 To a stirred solution of 5.2 grams of 4-(2-aminoethyl)-morpholine in 30 ccs. of benzene there are added, dropwise, 4.5 grams of 3-phenoxypropylbrornide. The mixture is refluxed for 16 hours with continuous stirring. On cooling, the separate hydrobromide of unchanged starting base is filtered oif. The basic products are extracted from the solution with the aid of hydrochloric acid. The acid aqueous extract is made alkaline and extracted repeatedly with benzene. The combined benzene extracts are worked up as described above.
• Example 5 In the same way as described in Example 1, but starting from Z-phenoxypropionyl chloride, the 4.[2-(2- phenoxypropylamino) ethylJ-mor-pholine dihydrochloride is obtained, which has a melting point of 188- 190 C.
• Example 6 To a solution of 10 grams of N-(phenoxyacetyl)-alanine in 135 ccs. of dry benzene are added with stirring 6.25 ccs. of triethylamine, 4.55 ccs. of ethyl chloroformate and, after about 15 minutes, 3.55 ccs. morpholine. Then the reaction-mixture is heated with continuous stirring on a steam bath for about two hours. The solution is allowed to cool, washed with 25 ccs, of 04 N hydrochloric acid and subsequently with 2 N sodium hydroxide. After drying, the benzene is removed by distillation. The residual, crude 4-[2-phenoxyacetylamino)- propionyl]-morpholine is reduced with lithium aluminum hydride in a manner similar to that described in Example 2.
• Example 7 A mixture of 13.0 grams of 4-(2-aminoethyl)-morpholine, 16.8 grams of 'phenoxyacetone and 60 ccs. of dry benzene is refluxed, the water formed being collected in a water separator.
• R is selected from the class consisting of hydrogen
• R and R are selected from the class consisting of hydrogen, lower alkyl, lower-alkoxy, trifluorornethyl, fiuoro, chloro, bromo and nitro, and methylene dioxy when R and R are taken together,
• R is selected from the class consisting of hydrogen and lower alkyl
• R and R together with the nitrogen atom form a member selected from the group consisting of Z- morpholino, Z-thiornorpholino, zepiperidino and Z- pyrrolidino, wherein Z is selected from vthe group consisting of hydrogen-and lower alkyl; and X and Y are selected frornzthe class consisting of straight and branched alkyleneichains having from v 2 to 4 carbon atoms; and

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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• 1962
  • 1962-07-25 US US212456A patent/US3239520A/en not_active Expired - Lifetime
  • 1962-11-16 DE DEN22367A patent/DE1283841B/de active Pending
  • 1962-11-16 CH CH1344762A patent/CH421103A/de unknown
  • 1962-11-16 DE DE19621470119 patent/DE1470119A1/de active Pending
  • 1962-11-16 CH CH1344862A patent/CH451148A/de unknown
  • 1962-11-19 BR BR144752/62A patent/BR6244752D0/pt unknown
  • 1962-11-19 DK DK497162AA patent/DK105205C/da active
  • 1962-11-19 BR BR144753/62A patent/BR6244753D0/pt unknown
• 1963
  • 1963-02-13 FR FR924587A patent/FR2468M/fr active Active

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